1. Field of the Invention
The invention relates to the production of compositions, particularly pharmaceutical compositions, containing an active principle capable of controlling the immune reactions of a host against allogeneic cells or tissues or of immunocompetent cells against an immunoincompetent or immunosuppressed host, particularly those immune reactions which are involved in the so-called host versus-graft reaction (HvGR) and so-called graft versus-host reaction (GvHR) or graft versus-host disease (GvHD), as well as immune reactions which are brought into play in bone marrow transplantation (BMT), i.e. when the host is transplanted with allogeneic or xenogeneic incompatible bone marrow.
2. Description of the Prior Art
Series of studies have been initiated in 1978 by the inventor relative to the bone-marrow-engraftment-promoting activity of bone-marrow-derived factors (Pierpaoli W. et al, Transplantation 1978; 26:456-458) and (Pierpaoli W. et al, J. Clin. and Lab. Immunol. 1985; 16:115-124). The initial observation was that the supernatant of a solution in which the bone marrow cells had been suspended (bone marrow supernatant: BM-SN) provided an engraftment-enhancing activity (Pierpaoli W. et al, Cell Immunol 1980; 52:62-72). This indicated the presence of factors able to modify the capacity of the bone marrow to be engrafted in an irradiated host for induction of permanent allogeneic or xenogeneic chimerism.
An extensive series of experiments further demonstrated that high-molecular-weight fractions obtained by ultrafiltration through porous membranes of the native BM-SN derived from rabbit marrow contained marrow-regulating factors (MRF) capable of exerting the same effect, i.e. of inducing hemopoietic chimerism across the H-2 barrier in the murine model (Pierpaoli W. et al, Cell Immunol 1981; 57:219-228). However, the results obtained are not easily reproduced, at least quantitatively; there is considerable variability in the results and the incidence of secondary disease is high. Moreover, induction of chimerism was not achieved in all of the murine H-2 combinations tested (Pierpaoli W. et al, J Lab Clin Immunol 1985;16:115-124).
More recently separation-and characterization of a specific component from rabbit bone-marrow-derived fractions, namely transferrin, has been reported. It is now considered to be responsible for the facilitation of allogeneic and xenogeneic bone marrow engraftment that had been achieved earlier with rabbit and bovine, marrow-derived fractions (European Patent application No. EP89403103.8/0426924 Pierpaoli W. et al, Cell Immunol 1981;57:219-228 and Pierpaoli W. et al, J Lab Clin Immunol 1985;16:115-124). Treating lethally irradiated C57BL/6 mice transplanted with bone marrow from BALB/c donors with iron-saturated human transferrin and conalbumin, resulted in remarkably stable engraftment, avoidance of GvHD and enduring chimerism in the majority of test animals (Pierpaoli W. et al, Cell Immunol 1991;134:225-234). But again, additional work seeking to evaluate the engraftment-promoting activity of human transferrin in other H2-incompatible murine combinations were not in all instances as successful.
No effect of human transferrin was observed in C57BL/6 mice grafted with marrow from C3H/He donors and in which marrow from C57BL/6 mice was transplanted into C3H/He mice. Accordingly, it seemed that the promoting effects of transferrin was rather varying according to the histogenetic H-2-type combination used, the promoting effect being maximal in C57BL/6 mice (H-.sup.2b) grafted with BALB/c (H-.sup.2d) marrow and absent in C57BL/6 mice grafted with C3H/HE (H-2.sup.k) marrow (Pierpaoli W. Nat. Immun. 1992; 11:356-365).
Thus if bone marrow or plasma-derived transferrins (Tf) profoundly affect engraftment of allogeneic or xenogeneic bone marrow in lethally irradiated mice and produce a lasting chimerism, it is now considered that the effect observed does not depend on levels or concentrations of Tf and from its saturation with iron, but rather on matching of donor Tf and tissue antigens in the immunosuppressed and transplanted host. The simultaneous presentation of Tf and antigens from a genetically specific donor (mouse, rat, human) in the course of immunoreconstitution results in fact in a state of donor-specific unresponsiveness or tolerance as shown by the acquired inability to mount an immune reaction against the same antigen--and Tf donor and, after bone marrow transplantation, to initiate a graft-versus-host reaction. Applicant thus presently considers that Tf possesses the unique ability to specifically induce specific allo- and xeno-tolerance by a mechanism presently under investigation. It would thus seem that Tf is a major element of the self-recognition and immune mechanisms and that it participates to the development and maintenance of self-tolerance during ontogeny and adulthood.
And indeed, the genetic polymorphism and heterogeneity of human serum transferrin can possibly be considered as directly mimicking the "immune personality" of a human individual: see the article titled "The Biology of transferrin" of de Jong G., Dijk J. P. and Van Ejk, H. C. Clinica Chimica ACTA, 1990, 1-46, Vol. 190.
This makes the invention all the more remarkable as apparently the desensitization of the immune specificity of the transferrins for use in the induction of immune tolerance in a recipient host with respect to antigens, e.g. organs or bone marrow of allogeneic or xenogeneic nature, can be achieved in far easier a manner as it could have seemed. Particularly, it has been found that transferrins, particularly human transferring, obtained from plasma mixtures resulting from the pooling of plasmas obtained from fairly limited numbers of individuals contained all that what is needed to ensure the required tolerance, in most, let alone all humans.